Abstract

Background

BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While
BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known
about somatic genome instability in breast cancer cells but not germline genome instability.

Methods

Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical
BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six
breast cancer-affected and two breast cancer unaffected members.

Results

We identified 23 deleterious mutations in the breast cancer-affected family members,
which are absent in the unaffected members. Multiple mutations damaged functionally
important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations
were germline mutation inherited from the ancestor(s) while only a few were somatic
mutation generated de novo.

Conclusion

Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast
cells.